Process for the preparation of 2,5-dimethyl-4,5-dihydrofuran-3-ol-4-one

ABSTRACT

2,5-DIMETHYL-4,5-DIHYDROFURAN-3-OL-4-ONE IS PREPARED BY CATALYTIC CYCLISATION OF HEXANE-3,4-DIOL-2,5-DIONE.

United States Patent Buchiet al.

[54] PROCESS FOR THE PREPARATION OF 2,5-DIMETHYL-4,5-DIHYDROFURAN-3-OL-4-0NE [72] inventors: George H. Buchi, 100 Memorial Drive, Cambridge,Mass. 02142; Edouard Demole, 100, rte de Chancy, Geneva, Switzerland;Albert Eschenmoser, 9, Bergstrasse, Kusnacht, Zurich, Switzerland; AlanF. Thomas, 16, Ch. de lEsplanade, Vernier, Geneva, Switzerland [451Sept. 26, 1972 [52] U.S. Cl. ..260/347.8 [51] Int. Cl. ..C07d 5/10 [58]Field of Search ..260/347.8

[56] References Cited OTHER PUBLICATIONS Paal, Berichte (1884) Vol. 17,p. 2756- 2767.

Dunlop et al., The Furans, New York, Reinhold Publ. Co. (1953) p. 35-37.

Hoffman et al., Chem. Abstracts (1966) Vol. 65, 2194f.

Primary ExaminerAlex Maze] Assistant Examiner-Bernard l. DentzAttorney-Pennie, Edmonds, Morton, Taylor and Adams [5 7] ABSTRACT2,5-dimethyl-4,5-dihydrofuran-3-ol-4-one is prepared by catalyticcyclisation of hexane-3,4-diol-2,5-dione.

6 Claims, N0 Drawings PROCESS FOR PREP TIGN 01* 2,5- DlMEYL-4,5-Dl i i"-3-0L-4-0NE This application is a division of our application Ser.

No. 736,268 filed June 12, 1968 now U.S. Pat. No. 3,558,174.

The present invention relates to a novel process for preparingh2,5-dimethyl-4,5-dihydrofuran-3-ol-4-one (hereinafter referred to asfuran derivative) which possesses valuable organoleptic properties andis, therefore, useful as a flavoring agent for foods and beverages. Theinvention furthermore relates to a new intermediate used in the saidnovel process and to methods for preparing it. I v

A known method for preparing 2,5-dimethyl-4,5- dihydrofuran-3-ol-4-oneconsists in heating rharnnose in the presence of piperidine acetate [cf.Proc. Am. Soc. Brewing Chemists 84 (1963)]. The starting rhamnose is arelatively expensive natural product which can be obtained only in smallinsufficient quantities and which, therefore, is not a suitable startingmaterial for the commercial production of the said dihydrofuranderivative.

Another known method for preparing 2,5-dimethyl-4,5'-dihydrofuran-3-ol-4-one comprises hydrogenolyzing acetylformoin bytreating the latter with hydrogen in the presence of a palladium-carboncatalyst and purifying the crude product by chromatography on silica[cf.I-lelv.Chim.Acta 49, 53 (1966)]. The yield of pure product is onlyabout percent of the theory.

A further known method for preparing 2,5-dimethyl- 4,5dihydrofuran-3-ol-4-one consists in catalytically hydrogenating-2,5-dihydroxymethyl-3,4-dibenzoxyfuran [cf. J. Org. Chem. 31, 2391(1966)]. The main disadvantage of this methodresides in the fact thatthe synthesis of the intermediate 2,5 -dihydroxymethyl-3,4-dibenzoxyfuran requires four chemical steps.-Furthermore, the overallyield of the desired product amounts to about 6.5 percent of the theoryonly. 6 The known methods described above are noneconomical laboratorymethods which cannot be applied to the production'of the saiddihydrofuran derivativeon a commercial scale. It has now been found thatthe furan derivative can be obtained easily and economically from newintermediates which are derived from cheap starting materials availablecommercially in unlimited quantities.

The process according to the invention comprises cyclizinghexane-3,4-diol-2,5-dione, which is a new compound, in the presence of acyclization catalyst.

Cyclization catalysts such as salts of organic carbox ylic acids withorganic nitrogen bases can be used. Suitable organic acids include,e.g., formic, acetic, propionic, malonic, maleic, tartaric and citricacid. Suitable organic bases include e.g. piperidine,dimethyl-piperidine, piperazine, picoline, morpholine or pyrrolidine. Apreferred cyclization catalyst is piperidine acetate. Alkali metal saltsof mineral acids can also be used as cyclization catalysts. These saltsinclude the so-called neutral salts which normally result from thecomplete neutralization by a metalic base of all the acidic functions ofa polybasic acid and the so-called acid salts which normally result fromthe complete neutralization of the acidic functions of a polybasic acid.The salts which can be used for the cyclization include the neutral" oracid salts of sodium, potassium, or lithium with sulphuric, carbonic,

phosphoric or boric acid, e.g., sodium sulphate, sodium bisulphate,sodium carbonate, sodium bicarbonate, sodium orthophosphate, sodiummonohydrogenphosphate, sodium dihydrogenphosphate or sodium borate.Mixtures of such salts can also be used as catalysts for thecyclization. Preferred catalysts of this type are sodium carbonate orbicarbonate, or mixtures of sodium orthophosphate, monohydrogenphosphateand dihydrogenphosphate.

The pH of the cyclization medium should preferably not be strongly acidor alkaline. A suitable pH range may vary from approximately 6-6.5 toapproximately 9. The cyclization can be performed outside of these pHlimits, but with too acidic conditions the cyclization is very slow andwith too alkaline conditions the yields are normally very low. The exactpH actually depends on the catalyst selected, but generally optimumresults are obtained when media with a pH of about 7-8 are used.

The cyclization can be performed in water or in a mixture of water witha water-miscible solvent, such as methanol, ethanol, dioxan,tetrahydrofuran or dimethoxyethane. Pure water is the preferred solvent.The cyclization can be performed at temperatures comprised between 20and 150C. but preferably at the reflux temperature of the reactionmixture under nitrogen or CO According to the inventionhexane-3,4-diol-2,5- dione, the cyclization gives the furan derivative,can be obtained by the reduction of pyruvaldehyde according to thefollowing scheme:

reduction CHa-COCHO OHCCO-CH The reduction can be carried out by meansof common reducing agents, e.g., stannous chloride, sodiumformaldehyde'sulphoxylate of chipped or powdered metals, such as tin,zinc, cadmium or iron, in the presence of hydrochloric, sulphuric oracetic acid. Zinc powder together with'acetic acid is a preferredreducing agent.

The reduction can be carried out in hydroxylic solvents, such asmethanol, ethanol, isopropanol or preferably water, at temperaturesbetween 20 and C. preferably at about 405 0C.

According to the invention hexane-3,4-diol-2,5- dione can also beprepared by a catalytic oxidation of 2 ,5-dimethyl-2,5-dimethoxy-3,4-dihydrofuran [obtained according to Bull. Soc. Chim. France 9971957)]according to the following scheme:

oxidation C1130 OCH: CH3COCHCHOOCH3 0 a. a... C 8 CH3 According to theinvention hexane-3,4-diol-2,5- dione can also be prepared by oxidizingacetol by means of an air'stream in a buffered aqueous solution. Theoxidation can be carried out at temperatures ranging from 40 to about150C. At the higher temperatures of this range pressure must be used forcarrying out the oxidation. Operating at about 90C. at a pH comprisedbetween 5 and 6 is preferred.

The invention is further illustrated by the following examples whereintemperatures are given in centigrade degrees.

EXAMPLE 1 Preparation of 2,5-dimethyl-4,5-dihydrofuran-3-ol-4- one a-l.Hexane-3,4-diol-2,5-dione A mixture of 680 g. of pyruvic aldehyde in theform of a 50 percent aqueous solution, 680 g. of ethanol and 500 g. ofglacial acetic acid were heated to 45, while stirring vigorously undernitrogen. Then 600 g. of powdered zinc were added portionwise within 1%hours, the temperature being maintained between 45 and 60. The solutionwas filtered, conconcentrated in vacuo, and the residue was taken up in500 ml. of warm ethyl acetate. The organic solution was filtered, andconcentration in vacuo caused the crystallization of 336 g. of crudeproduct which was then purified by recrystallization from ethyl acetateor by sublimation. The pure hexane-3,4-diol-2,5-dione melted at 89-90.a-2 Hexane-3,4-diol-2,5-dione A mixture of 625 g. of a 40 percentaqueous solution of pyruvic aldehyde, 815 ml. of water and 185 g. ofpure acetic acid were heated to 40-50, with vigorous stirring and undernitrogen. 220 g. of powdered zinc were then introduced portionwise,while maintaining the temperature between 40 to 50. The addition tookabout 3 hours, whereupon the mixture was further stirred for 2 hours atroom temperature. The unreacted metallic zinc was filtered, the filtrateconcentrated in vacuo at 3540, the zinc acetate was separated byfiltration and the filtrate diluted with 2 l. of water. it was thenproceeded to a continuous extraction with a mixture of ether-petroleumether (b.p. 3050), 2 1 (v/v), over a period of 1 week, then with amixture 9:1 (v/v) over a period of another week. After removal of thevolatile solvents the extracts yielded 198.5 g. (80 percent) of crudehexane-3,4-diol-2,5-dione which crystallized in the cold, and it waspossible to use it directly for the next cyclization step. b.Cyclization of hexane-3,4-diol-2,5-dione A solution of piperidineacetate was prepared by adding 1.49 g. of acetic acid and then dropwise1.2 ml. of piperidine to 17 ml. of water, the temperature beingmaintained below or at 20. Then 2.85 g. of hexane- 3,4-diol-2,5-dioneprepared according to the method described in paragraphs a1 or a-2 abovewere added under nitrogen. it was refluxed for 1 week under nitrogen andthen neutralized between and 10 by means of a 4 percent aqueous NaOHsolution. It was continuously extracted with ether overnight. After theusual drying and concentrating operations the ethereal extract yielded1.85 g. of crude furan derivative. By sublimation under a high vacuum(bath temperature 80) there were obtained 1.34 g. of sublimated productwhich was washed twice with a small amount of petroleum ether. Therewere thus obtained 1.27 g. (51 percent) of furan derivative, m.p. 7779,whose purity was confirmed by thin layer chromatography or bygas-chromatography.

EXAMPLE 2 Preparation of 2,5-dimethyl-4,5-dihydrofuran-3-ol-4- one a.Hexane-3,4-diol-2,5-dione A solution containing 7.16 g. (45.2millimoles) of 2,5-dimethyl-2,S-dimethoxy-dihydrofuran, 7.9 g. (64.5millimoles) of potassium chlorate, 0.25 g. (1.0 millimole) of osmiumtetroxide, 50 ml. of tetrahydrofuran and 100 m1. of water was heated for18 hours at 45-50 The solution was concentrated to dryness in vacuo andthe residue was extracted with ethyl acetate. The organic extracts werefiltered, dried over Na SQ, and, on concentration, yielded 6.9 g. ofcrude product which was directly used for the next cyclization step. Bycrystallization from a mixture of CHCl and CC], or from methylenechloride there was obtained the analytical sample having the followingspectral properties: 1R, 0 1710 cm'l (CHCl MNR, 8 2.25 ppm, 6 H, s; 4.25ppm, 2 H, s; 4.37 ppm, 2 H, s. Melting point: 58-60. b. Cyclization ofhexane-3,4-diol-2,5-dione A solution containing 5.4 g. ofhexane-3,4-diol-2,5- dione prepared according to the method described inparagraph (a) above, in 100 ml. of a solution saturated with sodiumbicarbonate was subjected to a continuous extraction with n-pentane overa period of one week and then with ether containing 10-15 percent ofpentane (v/v) equally over a period of one week. After the usualtreatment the combined extracts yielded 2.24 g. (51 percent) of furanderivative which was purified by sublimation according to the method ofExample 1. MNR spectrum (CDCl;,) 5 1.45 ppm, 3 H, d; 2.30 ppm, 3 H, s;4.55 ppm, 1 H, quartet; 7.65 ppm, 1 H, s.

EXAMPLE 3 Preparation of 2,5-dimethyl-4,5-dihydrofuran-3-ol-4- one a.Hexane-3,4-diol-2,5-dione A solution containing 22 g. of hydrate sodiumacetate, 0.67 g. of sulphuric acid, 200 ml. of water and 72.6 g. ofacetol was heated to 90, and there was passed through the solution overa period of hours a current of air divided into fine bubbles. Thesolution was concentrated to dryness in vacuo, taken up in 200 ml. ofwater and continuously extracted for 50 hours with ether containing 10percent (v/v) of petroleum ether (b.p. 3050). The usual treatment of theextract yielded 13.9 g. of crude product. It was possible to use itdirectly for the next cyclization step. b. Cyclization ofhexane-3,4-diol-2,5-dione A solution containing 10 g. ofhexane-3,4-diol-2,5- dione, prepared according to the method describedin paragraph (a) above, dissolved in 100 ml. of a molar aqueous solutionof trisodium phosphate was prepared. 20 ml. of a molar solution ofdisodium monohydrogenphosphate were added. The pH of the resultingsolution was adjusted to 8-8.2 by the addition of a molar solution oforthophosphoric acid (about 70-80 m1.) and the whole was heated for 24hours at It was then continuously extracted for 24 hours with a mixture1:1 (v/v) of ether and petroleum ether (b.p. 30-50). By means of theusual concentration boxylic acid with an organic nitrogen base.

3. Process according to claim 2 which comprises using piperidine acetateas a cyclization catalyst.

4. Process according to claim 1 which using, as a cyclization catalyst,an alkali metal salt of a polybasic mineral acid.

5. Process according to claim 1 which comprises using, as a cyclizationcatalyst, sodium carbonate, sodium bicarbonate or a mixture of sodiumorthophosphate, monohydrogenphosphate and dihydrogenphosphate.

6. Process according to claim 1, which comprises carrying out thecyclization in water at a pH comprised between 6 and 9 and at refluxtemperature.

2. Process according to claim 1 which comprises using as a cyclizationcatalyst a salt of an organic carboxylic acid with an organic nitrogenbase.
 3. Process according to claim 2 which comprises using piperidineacetate as a cyclization catalyst.
 4. Process according to claim 1 whichusing, as a cyclization catalyst, an alKali metal salt of a polybasicmineral acid.
 5. Process according to claim 1 which comprises using, asa cyclization catalyst, sodium carbonate, sodium bicarbonate or amixture of sodium orthophosphate, monohydrogenphosphate anddihydrogenphosphate.
 6. Process according to claim 1, which comprisescarrying out the cyclization in water at a pH comprised between 6 and 9and at reflux temperature.